Cancer remains a major cause of mortality and morbidity worldwide, despite recent success with drugs that provide survival benefit to patients. For most solid tumors, there is still a high rate of tumor recurrence and metastases associated with poor prognosis. Currently available drugs include cytotoxic chemotherapeutics, antiangiogenic agents, and targeted agents. The clinical benefit achieved with most of the currently available anticancer drugs is limited due to either development of drug resistance or intolerable toxicities that may affect a variety of organs (e.g., hematological toxicities, hepatotoxicity, nephrotoxicity, and neurotoxicity).
Cancer is a disease characterized by uncontrolled proliferation. Advances in understanding the signals that drive cancer are being made. During development and tissue remodeling, pluripotent stem cells serve as the source for differentiating cells to give rise to non-proliferating specialized cell types. A link between the characteristics of these stem cells and the rapid uncontrolled proliferation of tumors is becoming clear. One of the major developmental signaling axes is the Notch pathway. Notch signaling regulates cell-fate by mediating the differentiation of progenitor cells during development and self-renewal of adult pluripotent stem cells. Notch functions to maintain progenitor cells in a pluripotent rapidly proliferating state. The Notch pathway plays an important role in development differentiation and processes of hematopoiesis and lymphopoiesis. It is involved in generation, proliferation and differentiation of hematopoietic stem cells during embryonic development.
Notch gene amplification, chromosomal translocation or mutations lead to elevated Notch signaling, thereby imparting a tumor growth advantage by keeping tumor cells in a stem cell-like proliferative state. Therefore, there is a very strong correlation between mutation in the Notch signaling pathway and pathogenesis of malignancies.
The Notch proteins, represented by four homologs in mammals (Notch1, Notch2, Notch3, and Notch4), interact with ligands Delta-like 1, Delta-like 3, Delta-like 4, Jagged 1, and Jagged 2. After ligand binding, Notch receptors are activated by serial proteolytic cleavage events including intramembranous cleavage regulated by γ-secretase. Such a γ-secretase-processed Notch becomes active as a form called intracellular subunits (ICN). The ICN translocates to the nucleus and forms part of a large transcription complex involving the CSL (CBF-1, Suppressor of hairless, Lag) transcriptional regulator directly altering the expression of key proliferation- and differentiation-specific genes.
In addition, γ-secretase is involved in the intramembrane proteolytic processing of several other proteins, including amyloid precursor protein [APP], CD44 stem cell marker, and HER4 [ErbB4]). Blocking Notch signaling via γ-secretase inhibition produces a slower growing, less transformed, phenotype in human cancer cells in vivo. Importantly, this phenotype remains stable in the absence of further dosing. This type of novel treatment approach holds the potential to make cancer a more manageable disease without the strong side-effects of traditional cytotoxic drugs.
2,2-Dimethyl-N—((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N′-(2,2,3,3,3-pentafluoro-propyl)-malonamide (1) is disclosed in WO 2005/023772 as useful for the treatment of Alzheimer's disease.

Therefore, there is a need to develop new drugs/chemotherapy protocols to further improve the treatment available for cancer patients.